US4336256A - Pyridoindole derivatives - Google Patents

Pyridoindole derivatives Download PDF

Info

Publication number
US4336256A
US4336256A US06/184,070 US18407080A US4336256A US 4336256 A US4336256 A US 4336256A US 18407080 A US18407080 A US 18407080A US 4336256 A US4336256 A US 4336256A
Authority
US
United States
Prior art keywords
sub
compound
cooc
compounds
conhch
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/184,070
Inventor
Gabor I. Koletar
Jonathan B. Frost
Regis Dupont
Patrick Lardenois
Claude Morel
Henry Najer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthelabo SA
Original Assignee
Synthelabo SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthelabo SA filed Critical Synthelabo SA
Application granted granted Critical
Publication of US4336256A publication Critical patent/US4336256A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This invention relates to pyridoindole derivatives useful in therapy.
  • the pyridoindole derivatives provided by this invention are in the form of racemates or optically active isomers, and are compounds of the formula (i) ##STR2## in which n is 0 or 1, R 1 represents a hydrogen or halogen atom, an alkyl or alkoxy radical or the group CF 3 , R 2 represents either an alkoxycarbonyl radical or a radical CONHR 5 , in which R 5 is an alkyl, cycloalkyl or benzyl radical, a phenyl radical which can carry a substituent, or a hydrogen atom, R 3 is a hydrogen atom, an alkyl radical or an alkoxycarbonyl radical and R 4 is either a hydrogen atom or an acyl radical or an alkyl radical or a radical CONHR 6 , in which R 6 is a hydrogen atom or an alkyl, cycloalkyl, benzyl, phenyl or substituted phenyl radical, the alkyl and alkoxy radicals having
  • the pyridoindole derivatives are herein referred to for brevity as the "therapeutic compounds”.
  • Preferred therapeutic compounds are those in which R 1 is H, Cl, F, CH 3 , CH 3 O, CF 3 or Br, R 2 is COOCH 3 , COOC 2 H 5 , CONHCH 3 or CONHC 2 H 5 , R 3 is H, CH 3 or COOC 2 H 5 , R 4 is H, CH 3 , CONH 2 , CONalkyl or COCH 3 and n is 0 or 1, subject to the above-mentioned exception clause.
  • the invention provides processes for the preparation of the compounds as follows:
  • a process for preparing a derivative defined above in which R 2 is CONHR 5 from a compound defined above in which R 2 is an alkoxycarbonyl radical and/or a compound defined above in which R 4 is CONHR 6 , alkyl or acyl from a compound defined above in which R 4 is a hydrogen atom which comprises reacting the said starting compound with an amine R 5 NH 2 , isocyanate R 6 NCO, R 6 being other than a hydrogen atom, alkali metal cyanate or compound of formula acyl-L or alkyl-L, L being a leaving group for the reaction, respectively, R 5 and R 6 being as defined above and if desired converting a free base of a formula (I) into a pharmaceutically acceptable acid addition salt thereof.
  • acyl-L is conveniently a dianhydride of formula (acyl) 2 O.
  • a solution of 36.1 g (0.156 mol) of 5-chlorotryptamine hydrochloride in 350 ml of methanol is reacted with 20 g of methyl pyruvate.
  • the mixture is stirred for one week at ambient temperature.
  • the methanol is driven off on a rotary evaporator.
  • the residue is taken up in ethyl acetate.
  • the mixture is stirred for 15 minutes and the precipitate is then filtered off.
  • the precipitate is treated with a saturated solution of sodium bicarbonate and extraction is carried out with ethyl acetate. An insoluble material is removed by filtration.
  • the organic solution is decanted, washed, dried and evaporated on a water bath in vacuo.
  • the autoclave is heated at 100° C. for 5 hours.
  • the solvent is driven off and a white solid is obtained. It is recrystallised from ethanol.
  • reaction scheme is as follows: ##STR9## (1) 42.75 g (0.25 mol) of 3-ethoxycarbonylpyrid-2-one are placed in a round-bottomed flask and 500 ml of water are added. 15 g of KOH are added and the mixture is stirred at ambient temperature for 24 hours.
  • the therapeutic compounds prepared by way of examples, are shown in the following table.
  • the therapeutic compounds were subjected to various pharmacological experiments.
  • Mice of the CDl strain are kept in an oxygen-depleted atmosphere produced by creating a partial vacuum (190 mm of mercury, corresponding to 5.25% of oxygen).
  • the survival time of the animals is noted. This time is increased by agents which are capable of assisting the oxygenation of tissues and in particular of the brain.
  • the compounds studied are administered intraperitoneally in several doses, 10 minutes before the experiment. The percentage increases in the survival time, relative to the values obtained for control animals, are calculated.
  • the mean active dose (MAD) that is to say the dose which increases the survival time by 100%, is determined graphically.
  • the MAD of the therapeutic compounds varies from 13 to 26 mg/kg, administered intraperitoneally.
  • the anti-depressive activity was determined by the test for the antagonism towards the ptosis induced by reserpine (C. Gouret et al., J. Pharmacol. (Paris) 8, 333-350 (1977)).
  • mice Male, CDl Charles River, France, weighing 18-22 g simultaneously receive the products to be studied or the solvent (administered intraperitoneally) and the reserpine (4 mg/kg, administered subcutaneously).
  • the degree of palpebral ptosis is assessed for each mouse by means of a rating scale (0 to 4).
  • the mean rating and the percentage variation relative to the control batch are calculated for each dose.
  • the AD 50 namely the dose which reduces the mean ptosis score by 50%, relative to the control animals, is determined graphically.
  • the AD 50 varies from 2 to 10 mg/kg, administered intraperitoneally.
  • the compounds of the invention reduce the total duration of the sleep by 20 to 35%.
  • the therapeutic compounds which possess both an anti-anoxia action and a psychotropic action, can be used in therapy for the treatment of vigilance disorders, in particular for combating behavioural disorders which can be attributed to cerebral vascular damage and to cerebral sclerosis encountered in geriatrics, and also for the treatment of epileptic vertigo due to cranial traumatisms, and the treatment of depressive states.
  • the therapeutic compounds can be formulated in pharmaceutical compositions containing the compounds and/or their salts as active principles, in association with any excipients which are suitable for their administration, in particular their oral or parenteral administration.
  • the methods of administration can be oral and parenteral.
  • the daily posology can range from 10 to 1,000 mg.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Pyridoindole derivatives of formula ##STR1## n=0 or 1; R1 =H, Hal, alk, alk--O--, CF3 ; R2 =--COOalk; --CONHR5 (R5 =H or various substituents); R3 =H, alk, --COOalk; R4 =H, Ac, alk, --CONHR6 (R6 =H or various substituents), and acid addition salts, except certain known compounds, are useful in treating anoxia and depression and in psychotropic therapy. They are prepared from tryptamine or a derivative thereof by reaction thereof with a pyruvic ester or 3-ethoxycarbonyl-1,2-dioxo-1-ethoxypropane to form compounds in which R4 is H and R2 is --COOalk. These compounds are reacted with amines, isocyanates or usual N-acylating or N-alkylating reagents to prepare the other compounds.

Description

This is a Division of application Ser. No. 112,212 filed Jan. 15, 1980, now U.S. Pat. No. 4,272,539.
This invention relates to pyridoindole derivatives useful in therapy.
The pyridoindole derivatives provided by this invention are in the form of racemates or optically active isomers, and are compounds of the formula (i) ##STR2## in which n is 0 or 1, R1 represents a hydrogen or halogen atom, an alkyl or alkoxy radical or the group CF3, R2 represents either an alkoxycarbonyl radical or a radical CONHR5, in which R5 is an alkyl, cycloalkyl or benzyl radical, a phenyl radical which can carry a substituent, or a hydrogen atom, R3 is a hydrogen atom, an alkyl radical or an alkoxycarbonyl radical and R4 is either a hydrogen atom or an acyl radical or an alkyl radical or a radical CONHR6, in which R6 is a hydrogen atom or an alkyl, cycloalkyl, benzyl, phenyl or substituted phenyl radical, the alkyl and alkoxy radicals having from 1 to 4 carbon atoms and the cycloalkyl radicals having from 3 to 6 carbon atoms, with the exception of the compounds wherein simultaneously n=O, R1 =H, R2 =COO(Et or Me), R3 =H or CH3 and R4 =H, or n=1, R1 =H, R2 =COOC2 H5, R3 =H or CH3 and R4 =H, or n=1, R1 =H, R2 =CONHCH3, R3 =H and R4 =H, but including pharmaceutically acceptable acid addition salts of the above-defined compounds of formula (I).
The pyridoindole derivatives are herein referred to for brevity as the "therapeutic compounds".
Preferred therapeutic compounds are those in which R1 is H, Cl, F, CH3, CH3 O, CF3 or Br, R2 is COOCH3, COOC2 H5, CONHCH3 or CONHC2 H5, R3 is H, CH3 or COOC2 H5, R4 is H, CH3, CONH2, CONalkyl or COCH3 and n is 0 or 1, subject to the above-mentioned exception clause.
Examples of specifically preferred therapeutic compounds of formula (I) are given in a Table hereinafter and this Table should be construed as extending to the free bases and all pharmaceutically acceptable salts of the free bases.
The invention provides processes for the preparation of the compounds as follows:
1. a process for the preparation of a derivative defined above in which R3 is an alkyl or alkoxycarbonyl radical, which process comprises reacting a compound of the formula ##STR3## R1 being as defined above, with a compound of formula R3 CO(CH2)n COOalkyl, R3 being as defined above,
and the resulting compound (I), in which R2 is COOalkyl and R4 is a hydrogen atom of the formula ##STR4## and if desired this compound is reacted with an amine R5 NH2 to give the compounds (I) in which R2 is CONHR5, and if desired the resultant compound or compound (B) is reacted with an isocyanate R6 NCO to give the compounds (I) in which R4 is CONHR6, R6 being other than a hydrogen atom or with an alkali metal cyanate to give the compounds (I) in which R6 is a hydrogen atom or is N-acylated or N-alkylated by a compound of formula acyl-L or alkyl-L, L representing a leaving group for the reaction, to give the compounds (I) in which R4 is alkyl or acyl, the radicals n, R1, R3, R4, R5 and R6 having the meanings as defined above, and if desired a free base of formula (I) thus obtained is converted into a pharmaceutically acceptable acid addition salt thereof;
2. a process for the preparation of a derivative defined above in which R3 is a hydrogen atom and n is 1, which process comprises reacting a compound of the formula (A') ##STR5## R1 being as defined above, with the compound EtO--CO--CO--CH2 --COOC2 H5, saponifying the resulting diester of formula(B') ##STR6## R1 being as defined above, reacting the resulting diacid with an alcohol of formula alkyl--OH to give a compound (I) in which R2 is COOalkyl and R3 is a hydrogen atom R2 and R3 being as defined above, and, if desired, reacting this compound in the manner defined for reaction of compound (B) above and if desired a free base of formula (I) thus obtained is converted into a pharmaceutically acceptable acid addition salt thereof;
3. A process for preparing a derivative defined above in which R2 is CONHR5 from a compound defined above in which R2 is an alkoxycarbonyl radical and/or a compound defined above in which R4 is CONHR6, alkyl or acyl from a compound defined above in which R4 is a hydrogen atom, which comprises reacting the said starting compound with an amine R5 NH2, isocyanate R6 NCO, R6 being other than a hydrogen atom, alkali metal cyanate or compound of formula acyl-L or alkyl-L, L being a leaving group for the reaction, respectively, R5 and R6 being as defined above and if desired converting a free base of a formula (I) into a pharmaceutically acceptable acid addition salt thereof.
In all the above processes "L" in "alkyl-L" is preferably anion-forming and acyl-L is conveniently a dianhydride of formula (acyl)2 O.
By way of illustration of the processes of the invention, the compounds (I) can be prepared in accordance with the following reaction scheme. "ALK" is alkyl and the other symbols as defined above for formula (I) except where otherwise indicated. ##STR7##
The conversion of the ester (I) into the amide (I) in which R2 =CONHR5 is effected in the same manner as in reaction scheme 1; likewise, the addition of the radical R4 =CONHR6 onto the compounds (I) in which R2 =COOalk or CONHR5 is effected in the same manner as in scheme 1.
Alternatively the compounds (I) in which R1 is CF3 or Br can be prepared in accordance with a somewhat different process (see Example 8) adapted from the process described for R1 =H in Chem. Abstracts, 60, 5471h.
The compounds in which R3 =H and n=O can be obtained in accordance with the method of preparation described by Z. J. Vejdelek et al., J. of Med. and Pharm. Chem., Volume 3, No. 3 (1961), pages 427-440.
The following examples illustrate the invention. The microanalyses and the IR and NMR spectra confirm the structure of the compounds.
EXAMPLE 1--Ethyl 6-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate [n=1, R1 =6-CH3, R2 =COOC2 H5, R3 =H, R4 =H]
1. 52.62 g (0.25 mol) of 5-methyltryptamine hydrochloride are suspended in 250 ml of ethanol and the suspension is heated to the reflux temperature. 57.75 g of 3-ethoxycarbonyl-1,2-dioxo-1-ethoxypropane are suspended in 250 ml of ethanol, and 25 ml of concentrated hydrochloric acid are added dropwise in the course of 10 minutes. The latter suspension is added to the suspension of 5-methyltryptamine HCl, kept at the reflux temperature. The mixture is allowed to cool overnight. The solvent is removed by evaporation, the residue is dissolved in 400 ml of water and the solution is rendered alkaline with ammonia. After extraction with ethyl acetate, an oil is obtained which is chromatographed on a silica column. After elution with an 8/2 mixture of chloroform and ethanol, an oil is obtained which solidifies on trituration with petroleum ether. After recrystallisation from hexane, the compound obtained ##STR8## melts at 102°-103° C.
2. 45 g of the preceding compound are heated under reflux in 450 ml of a 10% strength aqueous solution of NaOH for 20 hours. Concentrated hydrochloric acid (100 ml) is added dropwise to the cooled reaction mixture in the course of 30 minutes. The resulting solid is filtered off and dried over P2 O5.
3. 99.6 g of the crude solid obtained above are heated under reflux in a mixture of 250 ml of ethanol and 20 ml of concentrated sulphuric acid for 9 hours. The mixture is left to stand overnight. The ethanol is removed by evaporation and the residual solid is rendered alkaline with ammonia. The basic solution is extracted with 3 times 300 ml of ethyl acetate. The extract is evaporated. An oil is obtained which gives a white solid on trituration with petroleum ether. The solid is filtered off and dried.
After recrystallisation from hexane, the compound obtained melts at 103° C.
EXAMPLE 2--Methyl 6-chloro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate [n=O, R1 =6-Cl, R2 =COOCH3, R3 =CH3, R4 =H]
A solution of 36.1 g (0.156 mol) of 5-chlorotryptamine hydrochloride in 350 ml of methanol is reacted with 20 g of methyl pyruvate. The mixture is stirred for one week at ambient temperature. The methanol is driven off on a rotary evaporator. The residue is taken up in ethyl acetate. The mixture is stirred for 15 minutes and the precipitate is then filtered off. The precipitate is treated with a saturated solution of sodium bicarbonate and extraction is carried out with ethyl acetate. An insoluble material is removed by filtration. The organic solution is decanted, washed, dried and evaporated on a water bath in vacuo.
The oily residue crystallises after a few days. After recrystallisation from toluene, the compound melts at 148° C.
EXAMPLE 3--Ethyl 1-methyl-2-methylaminocarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate [n=1, R1 =H, R2 =COOC2 H5, R3 =CH3, R4 =CONHCH3 ]
10.9 g (0.04 mol) of ethyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate are suspended in 200 ml of cyclohexane. 3 ml (0.04 mol) of methyl isocyanate are added. The mixture is heated under reflux for 1 hour. It is allowed to cool overnight in a refrigerator. The precipitate is filtered off. The product is recrystallised from ethanol.
Melting point=217° C.
EXAMPLE 4--Ethyl 2-aminocarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate [n=O, R1 =H, R2 =COOC2 H5, R3 =H, R4 =CONH2 ]
56.2 g (0.2 mol) of ethyl 2,3,4,9-tetrahydro-1H-pyrido[3,4b]indole-1-carboxylate are heated to about 60° C. in 1,000 ml of water. A solution of 15.2 g (0.234 mol) of pulverulent sodium cyanate in 200 ml of water is added all at once. The mixture is stirred for 15 minutes and then cooled to about 10° C. The aqueous reaction phase is decanted and the compound is washed with water and recrystallised from ethanol.
Melting point=215°-217° C.
EXAMPLE 5--1-Methyl-1-methylaminocarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole [n=O, R1 =H, R2 =CONHCH3, R3 =CH3, R4 =H]
4.8 g (0.02 mol) of methyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate are dissolved in 100 ml of ethanol saturated with methylamine. The solution is left at ambient temperature for 48 hours. The solvent is removed and the residue is then taken up in 20 ml of ethanol. The product is filtered off and washed with ethanol.
Melting point=230°-231° C.
EXAMPLE 6--6-Fluoro-1-methylaminocarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole [n=1, R1 =6-F, R2 =CONHCH3, R3 =H, R4 =H]
20 g of ethyl 6-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate (obtained in accordance with the process of Example 1) and 500 ml of ethanol saturated with methylamine are placed in an autoclave.
The autoclave is heated at 100° C. for 5 hours. The solvent is driven off and a white solid is obtained. It is recrystallised from ethanol.
Melting point=227° C.
EXAMPLE 7--6-Chloro-1-methylaminocarbonyl-1-methyl-2 -acetyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole [n=1, R1 =6-Cl, R2 =CONHCH3, R3 =CH3, R4 =COCH3 ]
3 g (0.0102 mol) of 6-chloro-1-methylaminocarbonyl-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole are dissolved in 30 ml of pyridine. 2 ml of acetic anhydride are added. The mixture is stirred at ambient temperature for 48 hours. It is evaporated and the pyridine is driven off. The residue is taken up in 20 ml of ethanol and the precipitate is filtered off. After recrystallisation from ethanol, the product melts at 214° C.
EXAMPLE 8--Ethyl 6-trifluoromethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate [n=1, R1 =6-CF3, R2 =COOC2 H5, R3 =H, R4 =H]
The reaction scheme is as follows: ##STR9## (1) 42.75 g (0.25 mol) of 3-ethoxycarbonylpyrid-2-one are placed in a round-bottomed flask and 500 ml of water are added. 15 g of KOH are added and the mixture is stirred at ambient temperature for 24 hours.
(2) A solution of 4-trifluoromethylaniline (42.25 g) in water (250 ml) and concentrated hydrochloric acid (55 ml) is reacted with 18.75 g of NaNO2 in 125 ml of water, at a temperature of 0° to 5° C. 50 g of CH3 COONa in 125 ml of water are then added.
(3) The compound obtained under 2 is added, in the course of 10 minutes, at 0°-5° C., to the compound obtained under 1. The mixture is stirred for 5 minutes. 75 ml of acetic acid are added. The mixture is stirred for 4 hours at ambient temperature. The product is filtered off and recrystallised from ethanol.
(4) 30 g of the compound ##STR10## are placed in a round-bottomed flask and 135 ml of glacial acetic acid and 68 ml of hydrochloric acid are added. The mixture is heated at the reflux temperature for 1 hour. The reaction mixture is cooled and poured onto 300 ml of ice. The resulting solid is recrystallised from ethanol.
(5) 15 g of 6-trifluoromethyl1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole are placed in a round-bottomed flask and 50 ml of POCl3 are added. The mixture is stirred at ambient temperature for 24 hours. 60 ml of ethyl ether are added and the product is filtered off. It is washed with 20 ml of ethyl ether and dried in vacuo over P2 O5 for 2 hours.
60 ml of methanol are placed in a round-bottomed flask and cooled to 0° C. 18.3 g of the compound obtained above are added in portions. The mixture is stirred at ambient temperature for 1 hour. Ethyl ether is added and a precipitate is obtained. After washing the compound, a white product (6) is obtained which melts at 220° C.
(6) 8.5 g of this compound are placed in a round-bottomed flask and 25 ml of ethyl acetoacetate are added. The mixture is heated under nitrogen at 140° C. for 8 hours. The reaction mixture is left to stand overnight. After washing, draining and drying, compound (7) is obtained, which melts at 144° C.
(7) 7.5 g of compound (7) are placed in a round-bottomed flask and 30 ml of ethanol are added. A solution of NaOH (1.25 g) in water (30 ml) is added. The mixture is heated at the reflux temperature for 1 hour. It is cooled in an ice bath. After it has been filtered off and dried in vacuo over P2 O5, compound (8) melts at 192° C.
(8) 5.2 g of compound (8), 13 ml of acetic acid and 50 ml of ethanol are placed in an autoclave. 0.43 g of platinum oxide is added and the mixture is stirred under hydrogen for 1 and a half hours under pressure. The mixture is filtered and the ethanol is driven off. The residue is rendered alkaline with NH4 OH and the solid is extracted with 4 times 100 ml of ethyl acetate. After drying, an oil is obtained which solidifies. After recrystallisation from ethanol, compound (I) melts at 140° C.
The therapeutic compounds, prepared by way of examples, are shown in the following table.
                                  TABLE                                   
__________________________________________________________________________
 ##STR11##                                                                
HCl = hydrochloride                                                       
m.s = methanesulphonate                                                   
                                         Melting                          
                                         point                            
Compound                                                                  
      R.sub.1                                                             
           R.sub.2     R.sub.3                                            
                             R.sub.4   n (°C.)                     
__________________________________________________________________________
1 (Exam-                                                                  
      6-CH.sub.3                                                          
           COOC.sub.2 H.sub.5                                             
                       H     H         1 103                              
ple 1)                                                                    
2     6-CH.sub.3                                                          
           COOC.sub.2 H.sub.5                                             
                       COOC.sub.2 H.sub.5                                 
                             H         1 102-103                          
3     6-CH.sub.3 O                                                        
           COOC.sub.2 H.sub.5                                             
                       H     H         1 181 (maleate)                    
4     6-CH.sub.3 O                                                        
           COOC.sub.2 H.sub.5                                             
                       COOC.sub.2 H.sub.5                                 
                             H         1 100                              
5     H    COOC.sub.2 H.sub.5                                             
                       COOC.sub.2 H.sub.5                                 
                             H         1 80-82                            
6     6-Cl COOC.sub.2 H.sub.5                                             
                       CH.sub.3                                           
                             H         1 104                              
7     6-Cl COOC.sub.2 H.sub.5                                             
                       H     H         1 240 m.s                          
8     6-Cl COOC.sub.2 H.sub.5                                             
                       COOC.sub.2 H.sub.5                                 
                             H         1 101                              
9     6-F  COOC.sub.2 H.sub.5                                             
                       H     H         1 229-230 m.s                      
10    6-F  COOC.sub.2 H.sub.5                                             
                       COOC.sub.2 H.sub.5                                 
                             H         1 197 HCl                          
11 (Exam-                                                                 
      6-Cl COOCH.sub.3 CH.sub.3                                           
                             H         0 148                              
ple 2)                                                                    
12    H    COOC.sub.2 H.sub.5                                             
                       H     CONH.sub.2                                   
                                       1 Oil                              
13 (Exam-                                                                 
      H    COOC.sub.2 H.sub.5                                             
                       CH.sub.3                                           
                             CONHCH.sub.3                                 
                                       1 217                              
ple 3)                                                                    
14 (Exam-                                                                 
      H    COOC.sub.2 H.sub.5                                             
                       H     CONH.sub.2                                   
                                       0 215-217                          
ple 4)                                                                    
15    H    COOC.sub.2 H.sub.5                                             
                       H     CONHC.sub.2 H.sub.5                          
                                       0 190-192                          
16    H    COOC.sub.2 H.sub.5                                             
                       H     CONHC.sub.3 H.sub.7n                         
                                       0 170-175                          
17    H    COOC.sub.2 H.sub.5                                             
                       H     CONHC.sub.4 H.sub.9t                         
                                       0 209-210                          
18    H    COOC.sub.2 H.sub.5                                             
                       H     CONHCH.sub.3                                 
                                       0 158-162                          
19    H    COOC.sub.2 H.sub.5                                             
                       H     CONHC.sub.3 H.sub.7i                         
                                       0 145-150                          
20    H    COOC.sub.2 H.sub.5                                             
                       H     CONHC.sub.6 H.sub.5                          
                                       0 164-168                          
21    H    COOC.sub.2 H.sub.5                                             
                       H                                                  
                              ##STR12##                                   
                                       0 160                              
22    H    COOC.sub.2 H.sub.5                                             
                       H     CONHC.sub.4 H.sub.9n                         
                                       0 140                              
23    6-CF.sub.3                                                          
           COOC.sub.2 H.sub.5                                             
                       H     H         1 140                              
24    6-Br COOC.sub.2 H.sub.5                                             
                       H     H         1 Oil                              
25    H    COOC.sub.2 H.sub.5                                             
                       CH.sub.3                                           
                             COCH.sub.3                                   
                                       1 194                              
26    H    COOCH.sub.3 CH.sub.3                                           
                             COCH.sub.3                                   
                                       0 238                              
27    H    COOC.sub.2 H.sub.5                                             
                       H     COCH.sub.3                                   
                                       0 211-212                          
28    6-F  COOCH.sub.3 CH.sub.3                                           
                             H         0 248                              
29    6-CH.sub.3                                                          
           COOCH.sub.3 CH.sub.3                                           
                             H         0 142                              
30    H    CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             H         1 182                              
31    6-Cl CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             H         1 212                              
32    H                                                                   
            ##STR13##  H     H         1 160                              
33    H                                                                   
            ##STR14##  H     H         1 166-168                          
34 (Exam-                                                                 
      6-F  CONHCH.sub.3                                                   
                       H     H         1 227                              
ple 6)                                                                    
35    6-Cl CONHCH.sub.3                                                   
                       H     H         1 232-233                          
36    6-CH.sub.3                                                          
           CONHCH.sub.3                                                   
                       H     H         1 216                              
37    6-CH.sub.3 O                                                        
           CONHCH.sub.3                                                   
                       H     H         1 190                              
38    H    CONHC.sub.2 H.sub.5                                            
                       H     H         1 148-149                          
39    H    CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             CH.sub.3  1 240                              
40 (Exam-                                                                 
      H    CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             H         0 230                              
ple 5)                                                                    
41    H    CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             CH.sub.3  0 207                              
42    6-Cl CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             H         0 230                              
43    6-F  CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             H         0 238                              
44 (Exam-                                                                 
      6-Cl CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             COCH.sub.3                                   
                                       1 214                              
ple 7)                                                                    
45    6-Cl CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             COCH.sub.3                                   
                                       0 280                              
46    6-Cl CONHC.sub.2 H.sub.5                                            
                       H     H         1 240                              
47    6-Cl                                                                
            ##STR15##  H     H         1 242                              
48    6-Cl CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             COCH.sub.3                                   
                                       1 214                              
49    6-Cl CONHCH.sub.3                                                   
                       H     COCH.sub.3                                   
                                       1 267                              
50    H                                                                   
            ##STR16##  H     H         1 189                              
51    H    CONHC.sub.2 H.sub.5                                            
                       CH.sub.3                                           
                             H         0 159                              
52    H                                                                   
            ##STR17##  CH.sub.3                                           
                             H         0 164                              
53    6-Cl CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             COCH.sub.3                                   
                                       0 280                              
54    6-CH.sub.3                                                          
           CONHCH.sub.3                                                   
                       CH.sub.3                                           
                             H         0 214                              
55    H    CONHCH.sub.3                                                   
                       H     H         0 158                              
56    H    CONH.sub.2  H     H         1 198-200                          
57    H    CONHCH.sub.3                                                   
                       H     H         0 158                              
__________________________________________________________________________
The therapeutic compounds were subjected to various pharmacological experiments.
In fact, the compounds were subjected to the test for the anoxia caused in mice by pressure reduction and to the test for the antagonism towards the ptosis induced by reserpine (C. Gouret et al., J. Pharmacol. (Paris) 8, 333-350 (1977)).
ANOXIA CAUSED BY PRESSURE REDUCTION
Mice of the CDl strain are kept in an oxygen-depleted atmosphere produced by creating a partial vacuum (190 mm of mercury, corresponding to 5.25% of oxygen).
The survival time of the animals is noted. This time is increased by agents which are capable of assisting the oxygenation of tissues and in particular of the brain. The compounds studied are administered intraperitoneally in several doses, 10 minutes before the experiment. The percentage increases in the survival time, relative to the values obtained for control animals, are calculated. The mean active dose (MAD), that is to say the dose which increases the survival time by 100%, is determined graphically.
The MAD of the therapeutic compounds varies from 13 to 26 mg/kg, administered intraperitoneally.
ANTI-DEPRESSIVE ACTIVITY
The anti-depressive activity was determined by the test for the antagonism towards the ptosis induced by reserpine (C. Gouret et al., J. Pharmacol. (Paris) 8, 333-350 (1977)).
Mice (male, CDl Charles River, France, weighing 18-22 g) simultaneously receive the products to be studied or the solvent (administered intraperitoneally) and the reserpine (4 mg/kg, administered subcutaneously).
After sixty minutes, the degree of palpebral ptosis is assessed for each mouse by means of a rating scale (0 to 4).
The mean rating and the percentage variation relative to the control batch are calculated for each dose.
For each product, the AD50, namely the dose which reduces the mean ptosis score by 50%, relative to the control animals, is determined graphically.
The AD50 varies from 2 to 10 mg/kg, administered intraperitoneally.
ACTION OF THE DURATION OF "SLEEP"
This action was determined by the influence of the compounds on the duration of the "sleep" induced in curarised rats by sodium 4-hydroxybutyrate (GHB); the rats are under artificial respiration and their electrocorticographic activity is recorded by means of cortical electrodes.
The compounds of the invention reduce the total duration of the sleep by 20 to 35%.
The pharmacological study of the therapeutic compounds shows that they are active in the test for the anoxia caused in mice by pressure reduction, whilst being only slightly toxic, and that they exert a significant waking action in the test for the "sleep" induced by sodium 4-hydroxybutyrate.
The therapeutic compounds, which possess both an anti-anoxia action and a psychotropic action, can be used in therapy for the treatment of vigilance disorders, in particular for combating behavioural disorders which can be attributed to cerebral vascular damage and to cerebral sclerosis encountered in geriatrics, and also for the treatment of epileptic vertigo due to cranial traumatisms, and the treatment of depressive states.
The therapeutic compounds can be formulated in pharmaceutical compositions containing the compounds and/or their salts as active principles, in association with any excipients which are suitable for their administration, in particular their oral or parenteral administration.
The methods of administration can be oral and parenteral.
The daily posology can range from 10 to 1,000 mg.

Claims (5)

We claim:
1. A compound of the formula ##STR18## wherein R1 =H, halogen, C1-4 alkyl, C1-4 alkoxy or CF3 ;
R2 =COO(C1-4 alkyl);
R3 =H, or COO (C1-4 alkyl); and
R4 =H, CH3 CO or CH3 ;
or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1, wherein said compound is ethyl(6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1)-acetate, or a pharmaceutically acceptable salt thereof.
3. A compound as claimed in claim 1, wherein said compound is ethyl(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1)-acetate.
4. A pharmaceutical composition for the treatment of anoxia and for providing a psychotropic effect comprising an effective amount of a compound as claimed in claim 1 in association with a pharmaceutically acceptable excipient.
5. A method of treating a patient for anoxia, comprising administering to the patient in need of such treatment a therapeutically effective dose of a compound as claimed in claim 1.
US06/184,070 1979-04-26 1980-09-04 Pyridoindole derivatives Expired - Lifetime US4336256A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7910654 1979-04-26
FR7910654A FR2455044A1 (en) 1979-04-26 1979-04-26 PYRIDO-INDOLES AND THEIR APPLICATION IN THERAPEUTICS

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US06/112,212 Division US4272539A (en) 1979-04-26 1980-01-15 Pyridoindole derivatives

Publications (1)

Publication Number Publication Date
US4336256A true US4336256A (en) 1982-06-22

Family

ID=9224797

Family Applications (2)

Application Number Title Priority Date Filing Date
US06/112,212 Expired - Lifetime US4272539A (en) 1979-04-26 1980-01-15 Pyridoindole derivatives
US06/184,070 Expired - Lifetime US4336256A (en) 1979-04-26 1980-09-04 Pyridoindole derivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US06/112,212 Expired - Lifetime US4272539A (en) 1979-04-26 1980-01-15 Pyridoindole derivatives

Country Status (15)

Country Link
US (2) US4272539A (en)
EP (1) EP0021857B1 (en)
JP (1) JPS55145687A (en)
AT (1) ATE2078T1 (en)
AU (1) AU528231B2 (en)
CA (1) CA1146942A (en)
DE (1) DE3061373D1 (en)
DK (1) DK16880A (en)
ES (2) ES487714A0 (en)
FR (1) FR2455044A1 (en)
GR (1) GR74393B (en)
IL (1) IL59131A (en)
NO (1) NO794272L (en)
PT (1) PT70699A (en)
ZA (1) ZA80243B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466688A (en) * 1994-10-20 1995-11-14 American Home Products Corporation Pyrido[3,4-B]indole derivatives as serotonergic agents
CN1046514C (en) * 1994-09-14 1999-11-17 西玛夫公司 Novel melatonin antagonist, its preparation method and its pharmaceutical use

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57123180A (en) * 1980-12-17 1982-07-31 Schering Ag 3-substituted beta-carboline, manufacture and psychotropic drug containing same
US4428880A (en) 1981-05-04 1984-01-31 S.A. Omnichem Azepino[4,5-d]indole derivatives and preparation thereof
DE3309596A1 (en) * 1982-08-05 1984-04-05 Basf Ag, 6700 Ludwigshafen 2-SUBSTITUTED 1- (3'-AMINOALKYL) -1,2,3,4-TETRAHYDRO-SS-CARBOLINE, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCT
DE3229215A1 (en) * 1982-08-05 1984-02-09 Basf Ag, 6700 Ludwigshafen 1- (HALOGENALKYL) -1,2,3,4-TETRAHYDRO-SS-CARBOLINE, THEIR PRODUCTION AND USE
US4719211A (en) * 1984-05-01 1988-01-12 American Home Products Corporation 2,3,4,9-tetrahydro-2-heteroarylalkyl-1H-pyrido(3,4-B)indoles having antihypertensive properties
JP2527319B2 (en) * 1986-12-25 1996-08-21 川研ファインケミカル株式会社 Method for producing 7-bromo-β-carboline derivative
DE3827727A1 (en) * 1988-08-16 1990-02-22 Boehringer Ingelheim Kg ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE OF SUCH CONNECTIONS FOR CARDIRO PROTECTION
FR2663935A1 (en) * 1990-06-27 1992-01-03 Adir NOVEL 1,2,3,4,5,6-HEXAHYDROAZEPINO [4,5-B] INDOLES AND 1,2,3,4-TETRAHYDROBETHACARBOLINES, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
DE4104257A1 (en) * 1991-02-13 1992-08-20 Boehringer Ingelheim Kg USE OF ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL ILLNESSES
FR2796644B1 (en) * 1999-07-23 2001-09-07 Adir NOVEL BETA-CARBOLINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4220774A (en) * 1978-10-26 1980-09-02 Omnium Chimique Vincadifformine synthesis process

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB841225A (en) * 1957-09-12 1960-07-13 Roche Products Ltd Novel quinolizine derivatives and process for the manufacture of same
GB1055203A (en) * 1964-09-16 1967-01-18 Ici Ltd -ß-carboline derivatives, a process for their manufacture, and compositions containing them
US4091102A (en) * 1975-08-22 1978-05-23 Endo Laboratories, Inc. Anti-depressant trans-hexahydropyrido[3,4-b]indoles
DE2960689D1 (en) * 1978-07-28 1981-11-19 Synthelabo Fluorene and fluoranthene derivatives, process for their preparation and their therapeutic application

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4220774A (en) * 1978-10-26 1980-09-02 Omnium Chimique Vincadifformine synthesis process

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1046514C (en) * 1994-09-14 1999-11-17 西玛夫公司 Novel melatonin antagonist, its preparation method and its pharmaceutical use
US5466688A (en) * 1994-10-20 1995-11-14 American Home Products Corporation Pyrido[3,4-B]indole derivatives as serotonergic agents
US5527794A (en) * 1994-10-20 1996-06-18 American Home Products Corporation Pyrido[3,4-b]indole derivatives as serotonergic agents

Also Published As

Publication number Publication date
IL59131A (en) 1983-10-31
NO794272L (en) 1980-10-28
PT70699A (en) 1980-02-01
FR2455044A1 (en) 1980-11-21
AU528231B2 (en) 1983-04-21
GR74393B (en) 1984-06-28
DK16880A (en) 1980-10-27
ES494263A0 (en) 1981-06-16
EP0021857A1 (en) 1981-01-07
ES8102124A1 (en) 1980-12-16
JPS55145687A (en) 1980-11-13
IL59131A0 (en) 1980-05-30
AU5463180A (en) 1980-10-30
CA1146942A (en) 1983-05-24
ES8105733A1 (en) 1981-06-16
DE3061373D1 (en) 1983-01-27
ATE2078T1 (en) 1983-01-15
ZA80243B (en) 1980-12-31
US4272539A (en) 1981-06-09
EP0021857B1 (en) 1982-12-22
FR2455044B1 (en) 1982-05-21
ES487714A0 (en) 1980-12-16

Similar Documents

Publication Publication Date Title
US4382938A (en) Imidazo[1,2-a] pyridine derivatives and their application as pharmaceuticals
US4336256A (en) Pyridoindole derivatives
NZ207156A (en) (2 quinazolinyl)-oxalkylamide derivatives and pharmaceutical compositions
KR910000416B1 (en) Method for preparing benzoxazolinone derivatives
NZ264063A (en) N-(2-phenylpyrid-3-yl)- and n-(4-phenylpyrimidin-5-yl)-n'-phenylurea derivatives and pharmaceutical compositions
PL175347B1 (en) Tricyclic pharmaceutically active heterocyclic amines
CS277611B6 (en) 3-(2,2,5,6-tetrahydropyridyl)-pyrrolopyridine derivatives
US4277476A (en) Derivatives of fluorenes and fluoranthenes and process for their preparation
US4358451A (en) Pyrimido- and imidazo-pyridoindole derivatives
US4767755A (en) 3-(acylaminomethyl)imidazo[1,2-a]pyridine derivatives and pharmaceutical compositions
US5084456A (en) Oxazolopyridine compounds
EP0964865B1 (en) Pharmaceutically active tricyclic amines
US5023256A (en) Pharmacologically active aminoimidazopyridines
US5155116A (en) Medicinal oxazolopyridine compounds
US4758559A (en) Pyrrolo[1,2-a] [4,1]benzoxazepine derivatives useful as calmodulin and histamine inhibitors
US4228168A (en) Azepino [1,2,3-lm]-β-carboline compounds and pharmaceutical composition thereof
EP1057829B1 (en) Novel compounds and pharmaceutical compositions containing the same
US4530843A (en) Isoindole amidoxime derivatives
EP0041630B1 (en) New 3h-naphtho(1,2-d)imidazoles, the process for preparing them, the compounds for use as antiinflammatory agents and compositions containing them
US4243665A (en) 2-Heterocyclylalkyl-6-methoxy-naphthalenes
US4990506A (en) 3-(acylaminomethyl)imidazo[1,2-a]pyridine derivatives and their application in therapy
JP3145364B2 (en) Novel compound and pharmaceutical composition containing the compound
EP0115920A2 (en) Pyrazino(2',3'-3,4)pyrido(1,2-a) indole derivatives
JPH08134044A (en) New pyrimidine compound, intermediate and their production
EP0145304B1 (en) Tetrahydro-beta-carboline derivatives and process for the preparation thereof

Legal Events

Date Code Title Description
STCF Information on status: patent grant

Free format text: PATENTED CASE